Aromatic C–H Bond Functionalization Induced by Electrochemically in

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Aromatic C−H Bond Functionalization Induced by Electrochemically in Situ Generated Tris(p‑bromophenyl)aminium Radical Cation: Cationic Chain Reactions of Electron-Rich Aromatics with Enamides Long-Ji Li,† Yang-Ye Jiang,† Chiu Marco Lam,‡ Cheng-Chu Zeng,*,† Li-Ming Hu,† and R. Daniel Little*,‡ †

College of Life Science & Bioengineering, Beijing University of Technology, Beijing 100124, China Department of Chemistry & Biochemistry, University of California at Santa Barbara, Santa Barbara, California 93106, United States

‡

S Supporting Information *

ABSTRACT: An effective Friedel−Crafts alkylation reaction of electron-rich aromatics with N-vinylamides, induced by electrochemically in situ-generated TBPA radical cation, has been developed; the resulting adducts are produced in good to excellent yields. In the “ex-cell” type electrolysis, TBPA is transformed to its oxidized form in situ and subsequently employed as an electron transfer reagent to initiate a cationic chain reaction. An easily recoverable and reusable polymeric ionic liquid−carbon black (PIL−CB) composite was also utilized as a supporting electrolyte for the electrochemical generation of TBPA cation radical, without sacrificing efficiency or stability after four electrolyses. Cyclic voltammetry analysis and the results of control experiments demonstrate that the reaction of electron-rich aromatics and Nvinylamides occurs via a cationic chain reaction, which takes place though an oxidative activation of a C−H bond of electron-rich aromatics instead of oxidation of the N-vinylamide as previously assumed.

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INTRODUCTION Activation and functionalization of C−H bonds to form new C−C and C−heteroatom bonds has emerged as an important method in organic chemistry because of its step efficiency and atom-economical characteristics.1 Among existing methods for C−H bond activation and functionalization, a direct oxidative activation using transition metal oxidants or transition metal catalysts in combination with co-oxidants has proven to be one of the most efficient options.2 However, because toxicity and isolation problems accompany the use of transition metal-based reagents, the development of metal-free, catalytic, oxidative functionalization chemistry is desirable.3 Direct electron transfer at an electrode provides an alternative, environmentally benign method for achieving C− H bond functionalization.4 For example, Yoshida and coworkers have developed an efficient electrochemical C−H oxidative amination method for the synthesis of aromatic primary amines via N-arylpyridinium ion intermediates.4a On the basis of the same strategy of electrooxidative C−H functionalization, they also achieved direct C−N bond coupling of imidazoles with aromatic and benzylic substrates,4b as well as alkene difunctionalization using halogen and chalcogen cation pools stabilized by DMSO.4c By utilization of the novel and innovative properties of a boron-doped diamond (BDD) electrode to generate oxyl spin centers, Waldvogel et al. have developed an efficient approach to phenol−arene crosscoupling reactions, forming novel mixed biaryls with high selectivity.4d−f © XXXX American Chemical Society

We are interested in oxidative activation and functionalization of C−H bonds via indirect electrolysis, using a redox catalyst that plays the role of the electron transfer agent.5 In this context, we have explored novel redox catalysts based upon the triarylimidazole scaffold. Among other uses, they have been employed for the oxidative activation of benzylic C−H bonds to afford the corresponding aldehydes, ketones, and benzoates.6 In addition, we have also applied simple halide ions as redox catalysts to achieve electrochemical C−H bond functionalization, thereby forming new C−N and C−C bonds.7 Considering the fact that large amounts of supporting electrolyte are frequently employed in organic electrosynthesis to ensure ionic conductivity and the efficient movement of charge, we have recently developed a PIL−CB composite, which permits an electrolysis to be performed without using a traditional supporting electrolyte, thereby reducing waste and simplifying separation and isolation of the product. One significant advantage of the PIL−CB composite is that it can be efficiently recovered and reused (Scheme 1).8 Among well-known organic redox catalysts, tris(pbromophenyl)amine (TBPA) is a versatile and powerful organic redox catalyst and has been widely employed to achieve a variety of processes, including, for example, the deprotection of thioacetals, cleavage of anisyl ethers, oxidation of aromatic side chains, [4+2] cycloaddition reactions,9 and Received: September 22, 2015

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The Journal of Organic Chemistry Scheme 1. Preparation of the PIL−CB Composite as a Supporting Electrolyte

Table 1. Optimization of Reaction Conditions entry

2a (mmol)

1a (mmol)

cat. (mol %)

yield (%)

1a 2a 3a 4b 5b

0.5 0.5 0.5 0.5 0.5

1.0 1.5 2.0 1.5 1.5

10 10 10 10 5

24 50 47 52 37

a

In-cell. A mixture of substrates 1a, 2a, and TBPA was added to the anodic compartment of a divided cell. Controlled potential electrolysis was conducted at 0.9 V vs Ag/AgNO3. bEx-cell. In a divided cell, the TBPA+• was prepared first, the power supply was shut off, and then substrates 1a and 2a were added to the anodic compartment at room temperature.

during the key step a total synthesis of a sesquiterpene called daucene.10 While much effort has been expended, C−H bond functionalization induced by electrochemically in situ-generated TBPA cation radical is limited. In contrast, stable TBPA cation radical salts have been employed to induce C−H bond functionalization. For example, Jia et al. reported the C−H bond functionalization of glycine derivatives to construct a quinolone skeleton with styrene,11 or 1,4-dihydropyridines with 1,3-dicarbonyl compounds.12 While stable TBPA cation radical salts such as tris(p-bromophenyl)aminium hexachloroantimonate are commercially available, the Lewis acidity of SbCl5, the decomposition product formed upon standing, can render it unsuitable for acid-sensitive substrates unless a hindered base is added as a scavenger.10,13c Thus, we chose to form the TBPA cation electrochemically in situ and subsequently use it to promote C−H bond functionalization. This strategy can increase reaction efficiency if the TBPA is recovered by simple chromatographic separation and reused in subsequent reactions. Herein, we (1) report that the in situ generation of TBPA radical cation does allow the activation of aromatic C−H bonds and induces their Friedel−Crafts alkylation with enamides, (2) demonstrate that a PIL−CB composite can serve as an effective supporting electrolyte in TBPA-mediated chemistry, thus avoiding the employment of a large amount of conducting salt, (3) investigated the mechanism of the coupling process using voltammetry, (4) demonstrate that the homogeneous electron transfer occurs initially between TBPA radical cation and electron-rich aromatics, instead of with an enamide, and (5) determine that the chemistry occurs via a cationic chain reaction pathway. To the best of our knowledge, this work represents the first example using TBPA as a mediator to activate aromatic C−H bonds and induce a cationic chain reaction. We believe that the combination of electrochemically in situ-generated TBPA cation radical and PIL−CB composite as a supporting electrolyte constitutes an attractive electrolytic system for catalytic electrosynthesis.

mixture by TLC revealed that vinylpyrrolidinone 1a was consumed quickly, whereas most of 2a remained intact, a 2:1 ratio of 1a to 2a was subsequently employed. To our delight, the desired adduct 3a did form, albeit in a 24% isolated yield (Table 1, entry 1). Increasing the amount of 1a to 3 equiv with respect to 2a improved the yield of 3a (Table 1, entry 2). Further increases did not improve the reaction (Table 1, entry 3). We note that the blue color of the TBPA cation radical is visible while charge is being passed and persists for at least 0.5 h once the current is turned off. This observation, coupled with previous literature, suggested that the reaction of 1a and 2a could proceed in a catalytic manner.13 We envisioned that 3a might be generated by a so-called “ex-cell” type of indirect electrolysis wherein the TBPA cation radical is first generated in situ and subsequently, in the same (or a separate) cell but without passing additional charge, be used to initiate an electron transfer with the substrates. If it is true, then electrocatalysis should be possible and the amount of current needed to conduct the chemistry should correspond only to that for the oxidation of a substoichiometric quantity of TBPA. Thus, side reactions, resulting from the anodic oxidation of substrates and solvent, as well as overoxidation of products, may be avoided. To demonstrate this idea, TBPA (10 mol %) was electrolyzed first. After passing 24 C of charge (2.5 F/mol with respect to 0.1 mmol of TBPA), the power supply was turned off and substrates 1a and 2a were added to the anodic compartment. After the mixture had been stirred at room temperature for ∼6 h, the desired adduct 3a could be isolated in a 52% yield (entry 4). In comparison with the in-cell procedure,5c the current yield increased, although the yield of 3a did not improve. Decreasing the amount of TBPA did not improve the outcome. For example, when the amount of TBPA was decreased to 5 mol %, the yield of 3a decreased to 37%; moreover, more than 10 h was required (Table 1, entry 5). At this stage of our investigation, we concluded that the optimal conditions involved the initial electrochemical generation of 10 mol % TBPA+•, followed by treatment of a mixture of electronrich aromatics and enamide in a molar ratio of 1:3 at room temperature (see Table 1, entry 4). With the optimal conditions in hand, we turned toward an exploration of the generality and scope of the reaction. As shown in Table 2, the reaction of 1a and other naphthalene alcohols bearing electron-donating and electron-withdrawing groups proceeded smoothly. For example, when naphthalene1,7-diol, 1b, was employed under the standard conditions, the desired product, 3b, was isolated in an 88% yield, while

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RESULTS AND DISCUSSION We commenced our studies by using vinylpyrrolidin-2-one, 1a, and naphthalene-2-ol, 2a, as model substrates and performing a controlled potential electrolysis (CPE) at 0.9 V versus Ag/ AgNO3, the oxidation peak potential of TBPA, in a divided cell using LiClO4/CH3CN as a supporting electrolyte, a platinum net as the working electrode, and an iron plate cathode (Scheme 2 and Table 1). Because monitoring of the reaction Scheme 2. Electrochemical Alkylation Reaction of Naphthalen-2-ol with Enamide 1a Mediated by TBPA

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Table 2. Scope of Electron-Rich Ar−H Partners for the Alkylation Reaction with Vinylpyrrolidin-2-one 1a Mediated by Preprepared TBPA+•

a Isolated yield following column chromatography. bReaction conditions: TBPA+• (0.1 mmol) was first electrochemically generated in a divided cell containing 10 mL of a LiClO4/CH3CN mixture (0.1 mol/L) using a platinum net anode and iron plate cathode and a controlled potential at 0.9 V vs Ag/AgNO3. Subsequently, vinylpyrrolidin-2-one 1a (3.0 mmol) and arenes 2 (1 mmol) were added, and the mixture was stirred at room temperature. cReaction conditions were similar to those described in footnote b, but using vinylpyrrolidin-2-one 1a (1.0 mmol), arenes 2 (1 mmol), and TBPA (0.05 mmol). dReaction conditions similar to those described in footnote c, but using 0.02 mmol of TBPA.

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The Journal of Organic Chemistry Table 3. Scope of Enamide Partners for the Alkylation Reaction Mediated by Pre-prepared TBPA+•

a

Reaction conditions are the same as those described in footnote b of Table 2. bReaction conditions are the same as those described in footnote c of Table 2.

Table 4. Alkylation Reaction of 2d with 1a in the Presence of the PIL−CB Composite as a Supporting Electrolytea

a

Reaction conditions: vinylpyrrolidin-2-one 1a (1.0 mmol), indole 2d (1 mmol) and TBPA (0.05 mmol) in 10 mL of CH3CN containing 0.3 M of PDDA(Tf2N) and 2 wt % of Super P carbon black, divided cell, platinum net anode and iron plate cathode, controlled potential at 0.9 V vs Ag/ AgNO3, room temperature.

Notably, the “ex-cell” electrolysis procedure was so effective that even 2 mol % TBPA led to an excellent yield of 3d, although a bit longer reaction time (2 vs 0.5 h using 5 mol % TBPA) was needed (Table 2, entry 9). Finally, it was observed that pyrrole, N-methylpyrrole, and 1,3,5-trimethoxybenzene were also compatible coupling partners (Table 2, entries 10− 12). To further explore the scope of the chemistry, other Nvinylamides were investigated, and the results are summarized in Table 3. It was observed that in contrast with enamide 1a, the reaction of N-vinylamides 1b and 1c with naphthalene-2-ol 2a gave lower yields of coupling products 3l and 3m (Table 3, entries 1 and 2). However, the chemistry was more effective in the case of indole. For example, the reaction of 1-vinylazepan-2one 1b with indole 2d gave 3n in a 78% yield (entry 3). In the case of N-vinylacetamide, 1c, coupling adduct 3o was obtained

substrate 1c, bearing an electron-withdrawing bromide group, gave a slightly lower yield of 3c (Table 2, entry 3). Indole derivatives also proved to be suitable candidates. Interestingly, under the standard conditions, the reaction proceeded rapidly and was complete in only 0.5 h, leading to the coupling product and the recovery of excess starting Nvinylpyrrolidin-2-one 1a. In an effort to minimize or entirely avoid the need to recover excess 1a, further optimization was conducted. When the ratio of 1a and indole was adjusted to 1:1 and the loading of TBPA reduced to 5 mol %, a 93% isolated yield of coupling product 3d was achieved in 0.5 h (Table 2, entry 4). Other indole derivatives, bearing electron-donating (MeO) or electron-withdrawing groups (Br and NO2), also proceeded smoothly to give the corresponding products in good to excellent yields (Table 2, entries 5−7). In the case of N-methylindole, adduct 3h was produced in an 86% yield. D

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The Journal of Organic Chemistry in a 93% yield. Notably, a double arylation product 3p was obtained in excellent yield when 2 equiv of indole was employed to react with 1c, an outcome that is similar to previous reports.13a,c The result is quite significant as structures of this sort are related to the soritins, substances that display unique anti-inflammatory properties.14 In the protocol described above, large quantities of LiClO4 were used to render the acetonitrile solution conductive. Of course, the presence of large quantities of an electrolyte leads to separation problems and the production of unwanted waste materials, which detracts from the notion that electroorganic synthesis is a “green and sustainable” process. On the basis of our research involving the use of a polymeric ionic liquid and carbon black composite as a reusable supporting electrolyte,8 we further investigated the electrocatalytic reaction employing the PIL−CB composite as a surrogate for a traditional supporting electrolyte. As shown in Table 4, the reaction of 1a with 2d proceeded smoothly and an 89% yield of 3d was isolated, nearly the same yield that was obtained using LiClO4 as the supporting electrolyte (note entry 4 of Table 2). Unlike the use of a traditional supporting electrolyte, 98% of the composite was recovered (Table 4, entry 1). To demonstrate the reusability of the PIL−CB composite, the reaction of 1a and 2d was repeated four times; each afforded an excellent and stable yield (∼90%) and permitted the recovery of >97% of the composite (Table 4, entries 2−4). Furthermore, cyclic voltammograms of the composite before electrolysis and after four electrolyses were nearly the same (Figure 1), thereby revealing that the composite is stable and can survive the electrochemical conditions and further highlighting its utility as a supporting electrolyte surrogate.

Scheme 3. Two Reaction Pathways of Enamides

enamides to iminium ion electrophiles,17 it is reasonable that triarylaminium13a,e and Fe(III) salts13c have also been utilized to induce Friedel−Crafts arylation of enamides with aromatics, to afford Markovnikov addition products regioselectively. To investigate the mechanism of the coupling reactions studied in this investigation, we first conducted cyclic voltammetry (CV) analysis of TBPA and related compounds. As shown in Figure 2 and Table 5, TBPA exhibited a well-

Figure 2. Cyclic voltammograms of TBPA and related compounds in 0.1 M LiClO4/CH3CN, using a Pt disk working electrode and a Pt wire and Ag/AgNO3 (0.1 M in CH3CN) as counter and reference electrodes, respectively, at a scan rate of 100 mV/s: (a) TBPA (2 mmol/L), (b) TBPA (2 mmol/L) and naphthalen-2-ol 2a (5 mmol/ L), (c) TBPA (2 mmol/L), naphthalen-2-ol 2a (5 mmol/L), and Nvinylpyrrolin-2-one 1a (20 mmol/L), (d) TBPA (2 mmol/L) and Nvinylpyrrolin-2-one 1a (10 mmol/L), (e) naphthalen-2-ol 2a (1 mmol/L), and (f) N-vinylpyrrolin-2-one 1a (1 mol/L).

resolved reversible oxidation wave (peak potential at 0.83 V vs Ag/AgNO3) and reduction wave (peak potential at 0.74 V vs Ag/AgNO3). Voltammograms of all electron-rich aromatics (2a−k) and N-vinylamides (1a−c) were also obtained. Each exhibited one or two irreversible oxidation wave(s) and no cathodic current in the potential scan range of 0.0−2.0 versus Ag/AgNO3 (0.1 M in CH3CN), a behavior that is typical of a so-called EC process (electrochemical step followed by a chemical step). The results reveal that the electrochemically generated cation radicals of these compounds are not stable on the time scale of the voltammetry measurements and instead engaged in chemical reactions with the solvent or other substrates. As shown in Table 5, the first oxidation potentials, EOX1, of the electron-rich aromatics (2a−k) were lower than

Figure 1. Cyclic voltammogram of the PIL composite (a) before electrolysis and (b) after four electrolyses at a platinum disk working electrode, platinum wire counter, and Ag/AgNO3 (0.1 M in CH3CN) reference electrodes, in 0.1 M LiClO4/CH3CN, at a scan rate of 0.1 V/ s.

Enamides are widely used as nucleophiles, leading to the introduction of an electrophile at the β-position (Scheme 3a).15 On the other hand, isomerization of enamides leads to the formation of iminium ion electrophiles, which can then react with a nucleophile (e.g., electron-rich aromatics) and introduce the nucleophile α to the amide nitrogen atom (Scheme 3b).16 Because Brønsted acids can promote the conversion of E

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The Journal of Organic Chemistry Table 5. Peak Potentials of TBPA and Related Compoundsa compound TBPA 1a 1b 1c 2a 2b

EOX1 (V)

EOX2 (V)

0.83 1.34 1.33 1.58 1.04 1.07

− −b −b −b −b −b b

compound 2c 2d 2e 2f 2g 2h

EOX1 (V)

EOX2 (V)

compound

EOX1 (V)

EOX2 (V)

1.25 0.97 0.86 1.07 1.26 1.02

− 1.40 1.23 1.29 −b 1.26

2i 2j 2k 3a 3d

1.30 1.13 1.32 1.05 1.07

−b −b −b −b −b

b

a CV conditions: TBPA and related compounds (1 mM) in 0.1 M LiClO4/CH3CN, platinum disk working electrode, platinum wire counter, and Ag/ AgNO3 (0.1 M in CH3CN) reference electrode. Scan rate of 0.1 V/s. bThere is only one oxidation peak in the range of 0.0−2.0 vs Ag/AgNO3.

Scheme 4. Control Experiments

Table 6. Natural and Mulliken Atomic Charges for 1a and Its Cation Radical

a

Atomic charges (both “natural” and “Mulliken”); values obtained from B3LYP/6-31+G(d) calculations.

those of the N-vinylamides (1a−c), implying that the initial electron transfer will preferentially occur between TBPA+• and the aromatics rather than the enamides. The electrochemical behavior of TBPA in the presence of Nvinylpyrrolin-2-one, 1a, and naphthalen-2-ol, 2a, further demonstrates that the electrochemically generated TBPA cation radical undergoes electron transfer with 2a. As shown in Figure 2 (curve b), a dramatic enhancement of the anodic current of TBPA (24 μA vs 55 μA) was observed and was accompanied by a decrease in the cathodic current when 2.5 equiv of naphthalen-2-ol 2a was added to the solution of TBPA in CH3CN. Because the oxidation peak potential of 2a appears at 1.04 V versus Ag/AgNO3, a value that is greater than that of TBPA (0.83 V vs Ag/AgNO3), the increase in the anodic peak current corresponds to a catalytic current that reflects turnover of the TBPA−TBPA+• redox couple.5c The observation indicates that the homogeneous electron transfer process between TPBA•+ and naphthalen-2-ol 2a occurs rapidly. When both N-vinylpyrrolin-2-one 1a (10 equiv) and 2a were added to the TBPA solution, the anodic current increased once again, this time from 55 to 87 μA (compare curves a−c). We suggest that the additional increase likely involves the formation of the cation radical of 2a, thereby increasing the acidity of the OH proton, followed by a protonation at the β-carbon of the vinylamide and subsequent capture. On the other hand, comparison of curves a and d reveals that the voltammogram for TBPA when recorded in the presence of N-vinylpyrrolin-2one 1a alone is nearly identical to that recorded for TBPA in its

absence. This outcome indicates that a direct electron transfer between N-vinylpyrrolin-2-one 1a and TBPA+• does not occur. That TBPA does not serve as an efficient redox catalyst for the anodic oxidation of 1a is reasonable when one compares the peak potentials of TBPA and 1a (curve f), the difference being sufficiently large (>0.6 V) to establish an insurmountable thermodynamic impasse. On the basis of the results described above, we conclude that the initial electron transfer occurs between TBPA+• and the aromatics rather than the enamide substrates. To gain additional insight into the reaction mechanism, a series of control experiments were performed. As shown in Scheme 4a, TBPA (5 mol %) was initially oxidized at its peak potential (0.9 V vs Ag/AgNO3) to form its cation radical; subsequently, 1a (1 mmol) and indole 2d (1 mmol) were added to conduct the alkylation reaction under an argon atmosphere. After routine workup, 3d was isolated in an 82% yield. The result rules out the possibility that oxygen regenerates TBPA+• and supports the idea that the reaction is a TBPA+•-induced chain process. Controlled potential electrolysis of the mixture of 1a and indole, 2d, in the presence of TBPA, conducted at the peak potential of indole (1.0 V vs Ag/AgNO3), also gave 3d in 82% yield (Scheme 4b). By virtue of the fact that 1a (EOX1 = 1.34 V vs Ag/AgNO3) is more difficult to oxidize than 2d (EOX1 = 0.97 V vs Ag/AgNO3) and that CPE was conducted at 1.0 V versus Ag/AgNO3, it is consequently safe to conclude that it is the electron-rich aromatic 2d, instead of 1a, that initially undergoes F

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transfer with TBPA+•, serve as Lewis acids. Both types of cation radical 2+• promote the conversion of the N-vinylamide to an iminium ion electrophile. Once formed, the electron deficient α-carbon is subsequently attacked by the electron-rich aromatic to afford a new cation radical, 4+•. From there, a second homogeneous electron transfer between 2 and 4+• produces coupling product 3 and regenerates 2+•. The regeneration of 2+• allows the chain propagation to proceed. In this manner, the electrochemical initiation (viz., the first electron transfer between TBPA+• and Ar−H) is excluded from the subsequent chain reaction processes. Because only a catalytic amount of charge is required to generate a substoichiometric amount of TBPA+•, ≫100% current yields are achieved.

electrochemical oxidation to form its cation radical, and subsequently reacting with 1a to generate final product 3d. In addition, examination of the products reveals that coupling occurs between a nucleophilic center of the aromatic and the αcarbon of the enamide, implying that the α-carbon serves as an electrophilic site. To account for this outcome, we recall that while voltammetry establishes that an iminium ion is not formed initially, the conversion of enamides to iminium ion electrophiles could possibly be promoted by the initial cation radical 2+•, which will discussed later. To gain additional insight, we calculated the atomic charges at both the α- and βcarbons of the neutral and cation radical forms of Nvinylpyrrolin-2-one (1a and 1a+•, respectively) using the B3LYP method and a diffuse 6-31+G(d) basis set. The results, displayed in Table 6, list both the natural and Mulliken atomic charges, each simply representing an alternative method for calculating charge. The fact that the largest charge resides on the β-carbon in the neutral form, 1a, is entirely consistent with its nucleophilic character. The cation radical is more interesting. Here, the atomic charge at the β-carbon is diminished relative to that of the neutral form (−0.518) but remains substantial (−0.209). The α-carbon on the other hand becomes a hole, with an atomic charge of +0.055 (natural, and +0.007 Mulliken). Thus, the α-carbon of the cation radical becomes an attractive location for attack by a nucleophilic aromatic coupling partner, in accord with the experimental outcome. On the basis of the CV analysis and the control experiments described above, we propose that the reaction of electron-rich aromatics with N-vinylamides mediated by electrochemically in situ-generated TBPA cation radical involves a cationic chain reaction pathway. Quite different from chemically preprepared triarylaminium salt- and Fe(III) salt-induced chain reaction of enamides and aromatics, in which isomerization of enamides to form iminium ion electrophiles is the first step,13 our electrochemical chain reaction starts with the formation of cation radical 2+• generated via a homogeneous electron transfer between electron-rich aromatics 2 and TBPA+•, which is generated electrochemically in situ. The formation of cation radical 2+• increases the acidity of the O−H (for naphthols 2a−c) or N−H (for N-unsubstituted indoles, 2d−f, or pyrrole, 2i) bond, which leads to a protonation of the N-vinylamide (Scheme 5). In the cases of 2h, 2j, and 2k, their corresponding cation radicals (2h+•, 2j+•, and 2k+•, respectively), formed from homogeneous electron

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CONCLUSIONS In summary, an effective electrochemical protocol for the Friedel−Crafts alkylation of electron-rich aromatics with Nvinylamides has been developed, and the corresponding adducts form in good to excellent yields. In the protocol, the TBPA cation radical is generated electrochemically in situ and subsequently employed as an electron transfer regent to initiate a cationic chain reaction. The reusable PIL−CB composite developed by us previously could be utilized as a supporting electrolyte for the electrochemical generation of TBPA cation radical, without sacrificing efficiency, and remained stable after four electrolyses. Cyclic voltammetry analysis and control experiments demonstrate that the reaction of N-vinylamides with electron-rich aromatics occurs through a cationic chain reaction mechanism, via initial oxidative activation of the electron-rich aromatics, instead of oxidation of the Nvinylamide as previously assumed. The results further demonstrate the versatility of TBPA as a redox mediator in indirect electrolysis. In addition, the combination of electrochemically in situ-generated TBPA cation radical and a PIL composite as a supporting electrolyte has proven to be an attractive electrolytic system for catalytic electrosynthesis. Their application to other types of reactions is underway in our laboratory.

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EXPERIMENTAL SECTION

Instruments and Reagents. All melting points were measured with an Electrothermal melting point apparatus and are uncorrected. IR spectra were recorded using KBr pellets. NMR spectra were recorded with a 400 MHz spectrometer (400 MHz 1H frequency, 100 MHz 13C frequency). Chemical shifts are given as δ values (internal standard, TMS). Coupling constants are reported in hertz. High resolution mass spectral data was obtained using the electrospray ionization method and an ion trap mass analyzer. Other chemicals and solvents were obtained from a commercial resource and used without further purification. Cyclic Voltammetry. Cyclic voltammograms were measured using a Princeton Applied Research 273A potentiostat/galvanostat equipped with electrochemical analysis software, using a conventional threeelectrode cell. The working electrode was a glassy carbon disk electrode (ϕ ∼ 3 mm). The auxiliary and reference electrodes consisted of a Pt wire and Ag/AgNO3 (0.1 M in CH3CN), respectively. Glassy carbon was polished with a polishing cloth before each measurement. All electrodes for CV experiments were obtained from CH Instruments, Inc. The concentration of all tested compounds was 1 mmol L−1, while that of the supporting electrolyte was 0.1 mol L−1. General Procedures for In-Cell Electrolysis. An H type cell equipped with a 4G porosity glass frit to separate the anode and cathode compartments was used. A platinum mesh (2 cm × 3 cm) served as the working electrode; an Fe plate served as the counter

Scheme 5. A Plausible Mechanism for the Cationic Chain Reaction

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DOI: 10.1021/acs.joc.5b02222 J. Org. Chem. XXXX, XXX, XXX−XXX

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The Journal of Organic Chemistry electrode, and a Ag/AgNO3 (0.1 M) electrode was used as the reference electrode. The solution of 0.1 M LiClO4/CH3CN was added to the two compartments (10 mL × 2), each equipped with a magnetic stir bar. Then the substrate 1a (1.5 mmol), 2a (0.5 mmol), and the mediator, TBPA (10 or 5 mol %), were added to the anodic compartment. After connection to the constant-voltage power supply, the electrolysis was performed at a potential of 0.9 V (vs Ag/AgNO3) and terminated when TLC analysis showed that the starting 1a had been consumed. Then the solvent was removed under reduced pressure, and extraction was conducted using CH2Cl2 (3 × 15 mL). The combined organic layers were washed with a saturated aqueous NaCl solution and dried over MgSO4. The purified product was obtained after column chromatography on silica gel using a solvent mixture of petroleum ether and ethyl acetate. General Procedures for Ex-Cell Electrolysis. An H type cell equipped with a 4G porosity glass frit to separate the anode and cathode compartments was used. A platinum mesh (2 cm × 3 cm) served as the working electrode; an Fe plate served as the counter electrode, and a Ag/AgNO3 (0.1 M) electrode was used as the reference electrode. The 0.1 M LiClO4/CH3CN solution was added to the two compartments (10 mL × 2), each equipped with a magnetic stir bar. Then the mediator, TBPA, was added to the working electrode compartment. The solutions were degassed with argon for 10 min before the electrolysis, and an argon atmosphere was maintained throughout. At 0 °C, electrolysis was performed at a potential of 0.9 V (vs Ag/AgNO3) and terminated when 2.5 F/mol (12 C) of charge had been consumed. The electrodes were then removed, and substrates 1 and 2 were quickly added to the anodic compartment. Under ambient conditions, the resulting solution was stirred until the TLC analysis showed that starting material 1 had been consumed. Then the solvent was removed under reduced pressure, and extraction was conducted using CH2Cl2 (3 × 15 mL). The combined organic layers were washed with a saturated aqueous NaCl solution and dried over MgSO4. The purified product was obtained after column chromatography on silica gel using a solvent mixture of petroleum ether and ethyl acetate. General Procedures for Ex-Cell Type Electrolysis Using the Composite as the Supporting Electrolyte. An H type cell equipped with a 4G porosity glass frit to separate the anode and cathode compartments was used. A platinum mesh (2 cm × 3 cm) served as the working electrode; an Fe plate served as the counter electrode, and a Ag/AgNO3 (0.1 M) electrode was used as the reference electrode. The preprepared PDDA(Tf2N)/CB composite dispersion8 was added in equal volumes to the anode and cathode compartments of the H type cell that was equipped with a magnetic stir bar in each compartment. Then the mediator, TBPA, was added to the anodic compartment. The solutions were degassed with argon for 10 min before the electrolysis, and an argon atmosphere was maintained throughout. Electrolysis was performed at 0 °C at a potential of 0.9 V (vs Ag/AgNO3) and terminated when 2.5 F/mol (12 C) of charge had been consumed. The electrodes were then removed, and substrates 1 and 2 were quickly added to the anodic compartment. Under ambient conditions, the reaction mixture was stirred until the TLC analysis showed that the starting 1 had been consumed. Then the solvent was removed under reduced pressure; extraction was conducted using CH2Cl2 (3 × 15 mL), and an extended period of stirring in DCM was conducted to maximize the separation and isolation of the crude product from the composite. The crude reaction mixture was rinsed with additional DCM; the combined DCM solutions were washed with water and brine, and the organic layer was dried over MgSO4. The purified product was obtained after column chromatography on silica gel using a solvent mixture of petroleum ether and ethyl acetate. Recovery of the Composite. Following vacuum filtration, the composite was collected, dried in a vacuum oven at 80 °C, and weighed periodically. Drying was continued until the mass of the composite remained constant. Regeneration of the Composite Dispersion. The recovered composite was once again converted into a stable dispersion via the

addition of acetonitrile and, if needed, sonication using a simple laboratory sonicator. Reuse of the Composite Dispersion. The regenerated composite dispersion was added to the H type cell as the electrolyte, and electrolysis was conducted as described above. 1-[1-(2-Hydroxynaphthalen-1-yl)ethyl]pyrrolidin-2-one (3a).13a Isolated as a white solid (67 mg, 0.26 mmol, 52% yield): 1H NMR (400 MHz, CDCl3) δ 1.97 (d, J = 7.6 Hz, 3H), 2.04−2.10 (m, 2H), 2.45−2.50 (m, 2H), 3.67−3.73 (m, 1H), 3.81−3.87 (m, 1H), 5.72 (q, J = 7.2 Hz, 1H), 7.23 (d, J = 9.2 Hz, 1H), 7.33 (t, J = 7.4 Hz, 1H), 7.47−7.51 (m, 1H), 7.72 (d, J = 8.8 Hz, 1H), 7.79 (d, J = 8.0 Hz, 1H), 8.05 (d, J = 8.8 Hz, 1H), 10.14 (s, 1H); 13C NMR (100 MHz, CDCl3) δ 16.8, 18.3, 31.5, 47.5, 48.6, 118.1, 121.5, 122.2, 122.7, 126.5, 129.2, 129.4, 130.2, 133.1, 154.9, 177.2. 1-[1-(2,7-Dihydroxynaphthalen-1-yl)ethyl]pyrrolidin-2-one (3b).13a Isolated as a white solid (119 mg, 0.43 mmol, 88% yield): 1H NMR (400 MHz, DMSO-d6) δ 1.65 (d, J = 6.8 Hz, 3H), 1.72−1.93 (m, 2H), 2.13−2.29 (m, 2H), 3.14−3.20 (m, 1H), 3.55−3.60 (m, 1H), 5.76 (q, J = 7.2 Hz, 1H), 6.84 (d, J = 8.4 Hz, 1H), 6.90 (d, J = 8.8 Hz, 1H), 7.32 (s, 1H), 7.54 (d, J = 8.8 Hz, 1H), 7.58 (d, J = 8.8 Hz, 1H), 9.56 (s, 1H), 9.65 (s, 1H); 13C NMR (100 MHz, DMSO-d6) δ 17.8, 18.0, 31.2, 44.4, 45.2, 105.3, 115.2, 115.6, 116.1, 123.5, 129.5, 130.4, 135.6, 155.3, 156.5, 173.6. 1-[1-(6-Bromo-2-hydroxynaphthalen-1-yl)ethyl]pyrrolidin2-one (3c).13a Isolated as a white solid (50 mg, 0.15 mmol, 30% yield): 1H NMR (400 MHz, DMSO-d6) δ 1.76 (d, J = 7.2 Hz, 3H), 1.78−1.90 (m, 2H), 2.08−2.50 (m, 2H), 3.14−3.20 (m, 1H), 3.54− 3.60 (m, 1H), 5.88 (q, J = 7.2 Hz, 1H), 7.20 (d, J = 8.8 Hz, 1H), 7.53 (d, J = 9.2 Hz, 1H), 7.72 (d, J = 9.2 Hz, 1H), 8.04 (s, 1H), 8.07 (d, J = 9.2 Hz, 1H), 10.02 (s, 1H); 13C NMR (100 MHz, DMSO-d6) δ 22.4, 22.8, 35.8, 48.9, 49.7, 120.5, 122.4, 125.6, 130.3, 133.7, 134.4, 134.8, 135.3, 137.2, 160.2, 178.3. 1-[1-(1H-Indol-3-yl)ethyl]pyrrolidin-2-one (3d).18 Isolated as a white solid (212 mg, 0.93 mmol, 93% yield): 1H NMR (400 MHz, CDCl3) δ 1.61 (d, J = 6.8 Hz, 3H), 1.79−1.84 (m, 1H), 1.90−1.95 (m, 1H), 2.44−2.49 (m, 2H), 2.86−2.92 (m, 1H), 3.26−3.32 (m, 1H), 5.81 (q, J = 6.8 Hz, 1H), 7.11 (t, J = 7.2 Hz, 1H), 7.15 (s, 1H), 7.23 (t, J = 8.0 Hz, 1H), 7.39 (d, J = 8.0 Hz, 1H), 7.65 (d, J = 7.6 Hz, 1H), 8.38 (s, 1H); 13C NMR (100 MHz, CDCl3) δ 16.7, 17.8, 31.8, 42.3, 42.7, 111.3, 115.8, 119.4, 119.8, 122.3, 122.3, 126.5, 136.6, 174.4. 1-[1-(5-Methoxy-1H-indol-3-yl)ethyl]pyrrolidin-2-one (3e).18 Isolated as a white solid (219 mg, 0.85 mmol, 85% yield, at room temperature): 1H NMR (400 MHz, CDCl3) δ 1.57 (d, J = 7.2 Hz, 3H), 1.74−1.94 (m, 2H), 2.39−2.50 (m, 2H), 2.84−2.87 (m, 1H), 3.24−3.27 (m, 1H), 3.79 (s, 3H), 5.78 (q, J = 6.8 Hz, 1H), 6.84 (dd, J = 8.8 Hz, 2.4 Hz, 1H), 7.10−7.13 (m, 2H), 7.25−7.27 (d, J = 8.8 Hz, 1H), 9.48 (s, 1H); 13C NMR (100 MHz, CDCl3) δ 16.7, 17.7, 31.9, 42.3, 42.8, 55.8, 100.7, 112.2, 112.5, 115.1, 123.2, 126.8, 131.8, 154.0, 174.6. 1-[1-(5-Bromo-1H-indol-3-yl)ethyl]pyrrolidin-2-one (3f).18 Isolated as a white solid (278 mg, 0.91 mmol, 91% yield, at room temperature): 1H NMR (400 MHz, CDCl3) δ 1.58 (d, J = 6.4 Hz, 3H), 1.79−1.96 (m, 2H), 2.47 (t, J = 8.2 Hz, 2H), 2.84−2.89 (m, 1H), 3.25−3.31 (m, 1H), 5.71 (q, J = 6.8 Hz, 1H), 7.16 (d, J = 2.0 Hz, 1H), 7.27−7.28 (m, 2H), 7.73 (s, 1H), 9.03 (s, 1H); 13C NMR (100 MHz, CDCl3) δ 16.7, 17.8, 31.7, 42.3, 42.6, 112.7, 113.2, 115.8, 121.9, 123.4, 125.4, 128.1, 135.2, 174.4. 1-[1-(5-Nitro-1H-indol-3-yl)ethyl]pyrrolidin-2-one (3g).18 Isolated as a yellow solid (164 mg, 0.60 mmol, 60% yield, at room temperature): 1H NMR (400 MHz, DMSO-d6) δ 1.54 (d, J = 6.8 Hz, 3H), 1.70−1.86 (m, 2H), 2.21−2.31 (m, 2H), 2.72−2.75 (m, 1H), 3.27−3.32 (m, 1H), 5.59 (q, J = 6.8 Hz, 1H), 7.53 (d, J = 8.8 Hz, 1H), 7.64 (s, 1H), 7.80 (dd, J = 8.8, 2.0 Hz, 1H), 8.45 (d, J = 1.6 Hz, 1H), 11.79 (s, 1H); 13C NMR (100 MHz, DMSO-d6) δ 21.9, 22.5, 36.2, 46.5, 46.6, 117.2, 121.0, 122.1, 122.8, 130.6, 132.4, 144.8, 145.8, 178.4. 1-[1-(1-Methyl-1H-indol-3-yl)ethyl]pyrrolidin-2-one (3h).18 Isolated as a yellow oil (208 mg, 0.86 mmol, 86% yield, at room temperature): 1H NMR (400 MHz, CDCl3) δ 1.60 (d, J = 6.8 Hz, 3H), 1.77−1.95 (m, 2H), 2.40−2.49 (m, 2H), 2.88−2.94 (m, 1H), 3.26−3.32 (m, 1H), 3.78 (s, 3H), 5.79 (q, J = 6.8 Hz, 1H), 6.99 (s, H

DOI: 10.1021/acs.joc.5b02222 J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry

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1H), 7.11 (t, J = 8.0 Hz, 1H), 7.25 (t, J = 7.2 Hz, 1H), 7.31 (d, J = 8.0 Hz, 1H), 7.63 (d, J = 8.0 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ 16.8, 17.8, 31.8, 32.8, 42.2, 42.6, 109.2, 114.6, 119.5, 119.7, 122.1, 126.7, 126.9, 137.2, 174.2. 1-[1-(1H-Pyrrol-2-yl)ethyl]pyrrolidin-2-one (3i).13d Isolated as a gray solid (112 mg, 0.63 mmol, 63% yield, at room temperature): 1H NMR (400 MHz, CDCl3) δ 1.55 (d, J = 7.2 Hz, 3H), 1.92−2.04 (m, 2H), 2.34−2.50 (m, 2H), 3.09−3.15 (m, 1H), 3.36−3.42 (m, 1H), 5.35 (q, J = 7.2 Hz, 1H), 6.10−6.12 (m, 2H), 6.74 (s, 1H); 13C NMR (100 MHz, CDCl3) δ 15.9, 17.7, 31.6, 42.6, 44.1, 105.4, 107.3, 118.1, 131.8, 175.5. 1-[1-(1-Methyl-1H-pyrrol-2-yl)ethyl]pyrrolidin-2-one (3j). Isolated as a colorless oil (132.5 mg, 0.69 mmol, 69% yield): 1H NMR (400 MHz, CDCl3) δ 1.51 (d, J = 7.2 Hz, 3H), 1.87−1.99 (m, 2H), 2.35−2.49 (m, 2H), 2.83−2.89 (m, 1H), 3.26−3.32 (m, 1H), 3.52 (s, 3H), 5.46 (q, J = 6.8 Hz, 2H), 6.06−6.08 (m, 1H), 6.14−6.15 (m, 1H), 6.61 (t, J = 2.0 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ 16.6, 17.8, 31.6, 33.8, 42.2, 42.2, 106.5, 107.4, 122.8, 131.1, 173.8; IR (KBr) 2977, 1681, 1494, 1420, 1285, 1208, 716 cm−1; HRMS (ESI positive) calcd for C11H16N2O [M + H]+ 193.1341, found 193.1332. 1-[1-(2,4,6-Trimethoxyphenyl)ethyl]pyrrolidin-2-one (3k).5 Isolated as a white solid (195 mg, 0.70 mmol, 70% yield): 1H NMR (400 MHz, CDCl3) δ 1.50 (d, J = 7.6 Hz, 3H), 1.80−1.98 (m, 2H), 2.26−2.39 (m, 2H), 3.23−3.28 (m, 1H), 3.51−3.58 (m, 1H), 3.81 (s, 9H), 5.85 (q, J = 7.2 Hz, 1H), 6.12 (s, 2H); 13C NMR (100 MHz, CDCl3) δ 17.2, 18.2, 31.5, 42.5, 44.4, 55.3, 55.7, 91.0, 109.7, 159.9, 160.4, 174.0. 1-[1-(2-Hydroxynaphthalen-1-yl)ethyl]azepan-2-one (3l).13a Isolated as a white solid (49.5 mg, 0.17 mmol, 35% yield): 1H NMR (400 MHz, CDCl3) δ 1.55−1.73 (m, 6H), 1.92 (d, J = 7.2 Hz, 3H), 2.60−2.65 (m, 2H), 3.58−3.60 (m, 2H), 5.75 (q, J = 7.2 Hz, 1H), 7.18 (d, J = 8.8 Hz, 1H), 7.32 (t, J = 7.6 Hz, 1H), 7.49 (t, J = 7.6 Hz, 1H), 7.71 (d, J = 8.8 Hz, 1H), 7.79 (d, J = 8.0 Hz, 1H), 7.98 (d, J = 8.8 Hz, 1H), 9.91 (s, 1H); 13C NMR (100 MHz, DMSO-d6) δ 19.0, 23.4, 28.7, 29.4, 37.1, 43.9, 48.41, 116.3, 119.8, 123.1, 123.2, 127.1, 128.9, 130.0, 134.6, 155.6, 173.2. N-[1-(2-Hydroxynaphthalen-1-yl)ethyl]acetamide (3m).13a Isolated as a white solid (30 mg, 0.27 mmol, 26% yield): 1H NMR (400 MHz, DMSO-d6) δ 1.50 (d, J = 8.8 Hz, 1H), 1.82 (s, 3H), 5.85 (q, J = 7.2 Hz, 1H), 7.16 (d, J = 8.8 Hz, 1H), 7.26−7.29 (m, 1H), 7.43−7.47 (m, 2H), 7.67 (d, J = 8.8 Hz, 1H), 7.78 (d, J = 8.0 Hz, 1H), 8.10 (d, J = 8.8 Hz, 1H), 8.13 (s, 1H), 9.88 (s, 1H); 13C NMR (100 MHz, DMSO-d6) δ 20.6, 23.2, 42.1, 119.1, 121.0, 122.7, 123.0, 126.6, 128.8, 128.8, 129.0, 132.3, 153.2, 168.7. 1-[1-(1H-Indol-3-yl)ethyl]azepan-2-one (3n).18 Isolated as a white solid (200 mg, 0.78 mmol, 78% yield): 1H NMR (400 MHz, CDCl3) δ 1.16−1.30 (m, 3H), 1.53 (d, J = 6.8 Hz, 3H), 1.67−1.71 (m, 3H), 2.62−2.64 (m, 2H), 3.02−3.19 (m, 2H), 6.33 (q, J = 6.8 Hz, 1H), 7.12 (t, J = 7.6 Hz, 1H), 7.15 (d, J = 1.2 Hz, 1H), 7.20 (t, J = 7.4 Hz, 1H), 7.38 (d, J = 8.0 Hz, 1H), 7.62 (d, J = 7.6 Hz, 1H), 8.45 (s, 1H); 13C NMR (100 MHz, CDCl3) δ 17.1, 23.5, 29.0, 30.1, 37.9, 42.9, 45.1, 111.2, 116.7, 119.7, 119.8, 122.3, 122.6, 126.7, 136.6, 175.6. N-[1-(1H-Indol-3-yl)ethyl]acetamide (3o).18 Isolated as a white solid (188 mg, 0.93 mmol, 93% yield): 1H NMR (400 MHz, CDCl3) δ 1.65 (d, J = 6.4 Hz, 3H), 1.99 (s, 3H), 5.46−5.52 (m, 1H), 5.74−5.75 (m, 1H), 7.13−7.14 (m, 2H), 7.24 (t, J = 7.6 Hz, 1H), 7.40 (d, J = 8.4 Hz, 1H), 7.68 (d, J = 8.0 Hz, 1H), 8.41 (s, 1H); 13C NMR (100 MHz, CDCl3) δ 14.3, 20.6, 21.1, 23.4, 42.1, 60.6, 111.7, 115.7, 117.5, 119.2, 119.5, 121.8, 122.2, 126.0, 129.6, 136.8, 169.8. 3,3′-(Ethane-1,1-diyl)bis(1H-indole) (3p).13b Isolated as a white solid (223 mg, 0.86 mmol, 86% yield): 1H NMR (400 MHz, CDCl3) δ 1.85 (d, J = 7.2 Hz, 3H), 4.72 (q, J = 7.2 Hz, 1H), 6.91 (d, J = 1.6 Hz, 2H), 7.08−7.12 (m, 2H), 7.20−7.24 (m, 2H), 7.36 (d, J = 8.0 Hz, 2H), 7.63 (d, J = 8.0 Hz, 2H), 7.81 (s, 1H); 13C NMR (100 MHz, CDCl3) δ 21.8, 28.2, 111.2, 119.1, 119.8, 121.3, 121.7, 121.8, 126.9, 136.7.

Article

ASSOCIATED CONTENT

S Supporting Information *

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.joc.5b02222. Copies of 1H and 13C NMR spectra of all compounds and HRMS spectra of new compound 3j (PDF)

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AUTHOR INFORMATION

Corresponding Authors

*E-mail: [email protected]. Fax: 86-10-67396211. Telephone: 86-10-67396211. *E-mail: [email protected]. Fax: 805-893-4120. Telephone: 805-893-3693. Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS This work was supported by grants from the National Natural Science Foundation of China (21272021 and 21472011) and the National Key Technology R&D Program (2011BAD23B01). C.-C.Z. and R.D.L. are grateful to the U.S. National Science Foundation-supported PIRE-ECCI program (OISE-0968399) and the Center for the Sustainable Use of Renewable Feedstocks (CenSURF), a National Science Foundation Center for Chemical Innovation (CHE-1240194), for fostering our international collaboration.

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REFERENCES

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DOI: 10.1021/acs.joc.5b02222 J. Org. Chem. XXXX, XXX, XXX−XXX

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DOI: 10.1021/acs.joc.5b02222 J. Org. Chem. XXXX, XXX, XXX−XXX